Download Hormone Control of Calcium Metabolism

Hormone Control of
Calcium Metabolism
Aims
„
„
Calcium Homeostasis
Hormone Control Calcium Metabolism
„
Vitamin D
PTH
Calcitonin
„
Other hormones
„
„
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โทร: 7578
Calcium homeostasis
„
Calcium and Phosphate function
Bone release Ca++
Bone incorporates Ca++
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
BLOOD CALCIUM
Kidney conserve Ca++
Intestine absorbs Ca++
INTESTINAL ABSORPTION
KIDNEYS
URINE
THE PRINCIPLE “OUT”
Ca++ is excreted in urine
Ca++ is excreted from diet
Parathyroid glands
Parathyroid hormone (PTH)
„
84-amino acids polypeptide hormone
PTH is released from the chief cells of
the parathyroid gland.
„ A decreased in plasma Ca2+mediates the
release of PTH through calcium sensing receptor
(CaSR).
„
„
PTH binds to PTH/PTHrP receptor.
„
2nd messenger of PTH is cAMP.
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PTH action (distal tubules)
PTH actions (Kidney)
Direct
PTH increases reabsorption of Ca2+in the
distal convoluted tubules.
„
PTH increases PO43 - and HCO3- excretion
„
PTH
in the urine.
TrpV 5&6: epithelium calcium channels
NCX: sodium/calcium exchanger
PTH actions (Kidney)
Indirect
PTH
„
1-α hydroxylase
25 HCC
PTH actions (Bone)
1,25 DHCC
Intestinal absorption of Ca2+
PTH acts on osteoblasts to inhibit the
synthesis of collagen (inhibition of bone
formation).
ƒ PTH acts on osteoblasts to stimulate
secretion of RANKL , which acts on the
osteoclasts to promote demineralization
and Ca2+release (osteoclastic bone
resorption)
RANKL: receptor activator of NF-kB ligand
PTH actions (Bone)
„
„
PTH also activates Ca2+pumps within the
surface osteoblasts to move Ca2+out of bone
fluid and into the extracellular fluid (ECF).
[Ca2+] ×[PO43 - ] = คาคงที่
[Ca2+]
[PO43 - ]
[Ca2+]
[PO43 - ]
Osteoblasts
RANKL
Osteoclast precursor cell
Osteoclast
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PTH actions
Parathyroid glands
Decrease blood Ca++
Increase blood Ca++
PTH actions (Bone)
PTH (basal level)
Osteoblasts
Bone formation
Osteoclasts
Bone resorption
Bone releases Ca++
Kidney conserve Ca++
Increase active Vit D
Intestine absorbs
Ca++
Bone remodeling
Abnormal PTH secretion
„
Vitamin D synthesis
PTH deficit
„
„
parathyroidectomy
Hypocalcemia signs and symptoms
SKIN
LIVER
7-DEHYDROCHOLESTEROL
„
PTH excess
„
Primary hyperparathyroidism
is the most common cause of hypercalcemia.
„The defect lies with the parathyroid tissue ex. adenoma
KIDNEY
VITAMIN D3
25(OH)VITAMIN D
25-HYDROXYLASE
1α-HYDROXYLASE
hν
„
„
VITAMIN D3
1,25(OH)2 VITAMIN D
25(OH)VITAMIN D
Secondary hyperparathyroidism
(25-HCC)
(1,25-DHCC)
The defect is from other tissue such as chronic renal disease.
„
„
(ACTIVE METABOLITE)
Hypercalcemia signs and symptoms
TISSUE-SPECIFIC VITAMIN D RESPONSES
Vitamin D mechanism of action
The action of Vit. D is mediated by altered gene
transcription resulting in the synthesis of specific
proteins.
VIT D / VDR
RNA POL
Ex: CaBPs, Vitamin
D3receptor
5’ UNTRANSLATED REGION
VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
IN THE NUCLEUS
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Vitamin D action (enterocyte)
Vitamin D action
ƒ GUT
ƒ
Ca2+ and PO4 3-absorption from the gut
epithelium
ƒ
Ca2+ binding protein (CaBP) or by affecting
Ca2+ transport directly
ƒ
plasma membrane Ca2+ ATPase pump Ca2+
(PMCA) from enterocyte to blood
Ca2+
Ca2+
Ca2+
TrpV 5 & 6
Ca2+
Ca2+
Ca2+
Ca2+
ƒ BONE
ƒ
Eletrochemical gradient
Ca2+
mineralization from blood Ca2+ to bone
Vitamin D action
ƒ KIDNEY
IMCal: Intestinal membrane calcium binding protein
TrpV 5&6: epithelium calcium channels
Abnormal Vitamin D secretion
„
ƒ
tubular calcium reabsorption, possibly by
the action of CaBP
ƒ PARATHYROID
ƒ Inhibit transcription of the PTH gene
(feedback regulation)
Rickets / Osteomalacia
„
Vitamin D deficit
„ Uncalcified osteoid tissue Clinical
syndromes broadly categorized as Rickets
and Osteomalacia.
„ Decreased blood calcium.
Vitamin D excess
„Hypercalcemia (rare).
Calcium, PTH, and Vitamin D
feedback loop
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca2+
NORMAL BLOOD Ca2+
FALLING BLOOD Ca2+
BONE RESORPTION
URINARY LOSS
STIMULATE PTH
1,25(OH)2 D PRODUCTION
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Calcitonin
Parafollicular cells
32 amino acids peptide.
„
Calcitonin is released from parafollicular
(C or clear cells) of the thyroid gland.
„
Increased plasma Ca2+can stimulate
calcitonin release.
„
cAMP is the second messenger in the secretory
process.
„
Calcitonin action
„
The exact physiologic role of calcitonin is
uncertain.
Calcium homeostasis
Calcitonin
Vit D
THE ONLY “IN”
DIETARY HABITS,
SUPPLEMENTS
„
BONE
„
„
the osteclastic activity.
KIDNEY
„
BONE
PTH
BLOOD CALCIUM
INTESTINAL ABSORPTION
Calcitonin
Active vitamin D
PTH
KIDNEYS
Ca2+excretion in urine.
Vit D
PTH
URINE
THE PRINCIPLE “OUT”
Sex hormones
Other Hormones
„
„
GH, IGFs
„Activate chondrocytes
„
intestinal Ca2+absorption.
„
renal PO43 – reabsorption.
Thyroid hormone
„Physiological level: Increase bone formation.
„
Excess: Increase bone resorption by
decrease1,25 DHCC and increase
renal Ca2+excretion.
Estrogen
Androgen
PTH action on bone
Bone resorption
PTH action on kidney
Ca2+ excretion
Bone formation
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Other Hormones
Glucocorticoids
„
Sex hormones
„
GI Ca2+absorption.
„
Renal Ca2+excretion.
„
PTH.
Osteoporosis
Osteoporosis
Blood Calcium Function
Structure of bone and teeth
„
„
Hormone secretion and hormone action
„
Neurotransmission
„
Muscle contraction
„
Blood Clotting
Blood Calcium
„
Blood calcium are tightly regulated at
approximately 10 mg/dl.
Blood Phosphate Function
Structure of bone and teeth
„
„
A covalent modifier of the activity of numerous
enzymes.
„
A component of many intermediates in glucose
metabolism eg G-6-P.
„
A component of all high energy transfer
compounds eg ATP, NADP.
Hypocalcemia: sign and
symptoms
„
NEUROMUSCULAR: INVOLUNTARY
MUSCLE CONTRACTION (TETANY), 7TH CRANIAL
NERVE EXCITABILITY (CHVOSTEK’S SIGN),
NUMBNESS AND TINGLING IN FACE, HANDS,
AND FEET, TROUSSEAU’S SIGN
„
CNS: IRRITABILITY, SEIZURES
CARDIOVASCULAR: QT PROLONGATION
„
ON ECG
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Hypercalcemia: sign and
symptoms
„
CNS: lethargy, depression, decreased alertness,
„
GI: anorexia, constipation, nausea, and vomiting
RENAL: diuresis, impaired concentrating ability,
Integrated regulation of
calcium and phosphate
confusion, and coma
„
dehydration. Hypercalciuria is a risk for kidney
stones.
„
SKELETAL: most causes of hypercalcemia are
associated with increased bone resorption, and thus,
fracture risk
„
CARDIOVASCULAR: shortened QT interval
Plasma calcium
Trousseau’s sign
PTH secretion
Plasma Phosphate
Renal Phosphate
1,25 DHCC
INTESTINAL ABSORPTION
BONE RESORPTION
Urine
calcium
Plasma
calcium
Plasma
phosphate
Urine
phosphate
Calcitonin secretion
Ca2+
Chvostek’s sign
CaSR
PTH
PTH
Gq +Gi
-
pro-PTH
Down stream
signaling pathway
prepro-PTH
PTH mRNA
PTH gene
Nucleus
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Ca2+
1,251,25-Vit D
CaSR
PTH
PTH
Gq +Gi
-
pro-PTH
Down stream
signaling pathway
prepro-PTH
PTH mRNA
- +
PTH gene
CaSR gene
Nucleus
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